The long term goal of the proposed research is to discover the molecular basis for life-long tooth succession in reptiles and to apply this knowledge to the regeneration of human teeth. The post-doctoral fellow will be using a unique model, the leopard gecko, for this project. There are two main benefits to using reptiles as opposed to the more typical model, the mouse. First, reptiles are amniotes and thus share a common ancestry with mammals. What we learn in reptiles is relevant for humans. Second, tooth replacement in reptiles is on-going, independent of wear or injury and is rapid (30-90 days) thus it is feasible to study the process in a lab setting. In contrast, mammals have at most two sets of teeth and usually the second generation continues to form well into the post-natal period. The first question to be addressed is what is the precise timing and pattern of tooth replacement in healthy adult reptiles? To answer these questions, the leopard gecko is used as the model. These animals are easy to handle and it is possible to adapt many dental procedures used for humans to their smaller mouths. Miniature, serial wax bites and ?CT scans will be taken over a 6 month period and measurements of when teeth are lost and replaced will be taken. The tooth replacement phenotypes will then be correlated with the expression of genes in the dental tissues. We are interested in finding genes that are periodically expressed along the length of the jaw since some of these may coordinate tooth spacing and timing of induction of replacement teeth. The second question to be addressed is what are the long term sequelae of disrupting the activity of the dental lamina on the patterns of tooth replacement? To answer this question, micro surgeries will be carried out in adult geckos including cutting of the dental lamina. The outcomes are predicted to be a change in the spacing or rate of tooth replacement that can be traced back to molecular changes in the dental epithelium. The third and final question to be asked is what are the molecular controls of tooth patterning and induction during embryonic initiation and adult replacement? The roles of two candidate molecules will be studied. These two pathways, called Wingless related (Wnt) and Notch were selected in part because mutations in Wnt increase or decrease tooth number in humans, and because Notch- Delta signalling is known to regulate cell fate decisions between adult stem cell renewal and differentiation along with its role in regulating developmental clock mechanisms. To mirror the human condition, to look for evidence of homeostatic switches regulating tooth renewal, activators or inhibitors of Wnt and Notch will be injected into eggs and the effects on tooth epithelial growth and patterning will be studied. The synergistic research partnership between the applicant/postdoctoral fellow and supervisor will one day lead to more natural ways to replace teeth lost to disease or injury.